Positive and Negative Regulation of IL-17 in Experimental Arthritis

描述（由申请人提供）：白细胞介素(IL)-17已成为类风湿关节炎（RA）和关节炎模型发病过程中的关键炎症细胞因子。产生IL-17的CD4+T细胞最近被确定为Th细胞的一个独特亚群，并命名为Th17。Th17亚群从初始CD4+ T细胞分化需要IL-6和转化生长因子(TGF)-p的刺激。IL-23是Th17克隆扩增所必需的。干扰素(IFN)-y、IL-4、IL-27、IL-25和IL-2负性调节Th17的发育。我们对小鼠胶原诱导关节炎（CIA）模型的初步研究表明，在II型胶原（Cll）免疫应答中，CIA耐药的C57BL/6 （B6）小鼠高表达IFN-y和低表达IL-17，而CIA敏感的DBA/1小鼠低表达IFN-y和高表达IL-17。此外，IFN-y抑制Cll刺激IL-17的产生。IFN-y基因敲除B6小鼠IL-17反应显著增强，并出现由IL-17介导的CIA。RORyt是一种孤儿核激素受体，被认为是IL-17的主转录因子。我们发现过表达RORyt显著增加CD4+ T细胞产生IL-17。本提案的目的是确定IFN-y介导的IL-17抑制机制以及关节炎期间积极调节IL-17产生的因子。我们计划通过关注IFN^y对RORyt表达和与IL-17基因启动子结合的影响，研究DBA/1小鼠IFN-y低应答的机制，以及IFN-y介导的IL-17抑制的细胞和分子机制。最后，使用RORyt转基因小鼠和Cll TCR转基因小鼠，我们将研究哪些细胞因子是关节炎源性Th17细胞发育和关节炎表达和慢性所需要的。了解关节炎模型中关节炎源性Th17细胞如何被调控的细节，将为通过靶向调节IL-17表达的因子来设计新的RA治疗方案提供有用的信息。

DESCRIPTION (provided by applicant): Interleukin (IL)-17 has emerged to be a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA) and arthritis models. CD4+T cells producing IL-17 has recently been identified as a distinct subset of Th cells and designated Th17. The differentiation of Th17 subset from naive CD4+ T cells requires stimulation in the presence of IL-6 and transforming growth factor (TGF)-p. IL-23 is required for Th17 clonal expansion. Interferon (IFN)-y, IL-4, IL-27, IL-25 and IL-2 negatively regulate Th17 development. Our preliminary studies in murine collagen-induced arthritis (CIA) model showed that in response to collagen type II (Cll) immunization, CIA resistant C57BL/6 (B6) mice expressed high IFN-y and low IL-17 while CIA susceptible DBA/1 mice expressed low IFN-y and high IL-17. Moreover, IFN-y suppressed Cll stimulated IL-17 production. IFN-y knockout B6 mice displayed significantly enhanced IL-17 response and developed CIA that was mediated by IL-17. RORyt is an orphan nuclear hormone receptor that has been implicated as master transcription factor for IL-17. We showed that overexpression of RORyt markedly increased IL-17 production by CD4+ T cells. The goals of this proposal are to define the mechanisms of IFN-y mediated suppression of IL-17 and factors positively regulate IL-17 production during arthritis. We plan to investigate the mechanisms for low IFN-y response in DBA/1 mice and cellular and molecular mechanisms of IFN-y mediated suppression of IL-17 by focusing on effects of IFN^y on RORyt expression and binding to IL-17 gene promoter. Finally, using RORyt transgenic mice and Cll TCR transgenic mice we will examine what cytokines are required for development of arthritogenic Th17 cells and arthritis expression and chronicity. Understanding the details of how arthritogenic Th17 cells are regulated during arthritis models will provide useful information for novel therapeutic design in RA by targeting factors regulating IL-17 expression.